Abstract
BackgroundThe genetic changes in gastric adenocarcinoma are extremely complex and reliable tumor markers have not yet been identified. There are also remarkable geographical differences in the distribution of this disease. Our aim was to identify the most differentially regulated genes in 20 gastric adenocarcinomas from a Norwegian selection, compared to matched normal mucosa, and we have related our findings to prognosis, survival and chronic Helicobacter pylori infection.MethodsBiopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 20 patients immediately following surgical resection of the tumor. Whole genome, cDNA microarray analysis was performed on the RNA isolated from the sample pairs to compare the gene expression profiles between the tumor against matched mucosa. The samples were microscopically examined to classify gastritis. The presence of H. pylori was examined using microscopy and immunohistochemistry.Results130 genes showed differential regulation above a predefined cut-off level. Interleukin-8 (IL-8) and Claudin-1 (CLDN1) were the most consistently up-regulated genes in the tumors. Very high CLDN1 expression in the tumor was identified as an independent and significant predictor gene of reduced post-operative survival. There were distinctly different expression profiles between the tumor group and the control mucosa group, and the histological subsets of mixed type, diffuse type and intestinal type cancer demonstrated further sub-clustering. Up-regulated genes were mapped to cell-adhesion, collagen-related processes and angiogenesis, whereas normal intestinal functions such as digestion and excretion were associated with down-regulated genes. We relate the current findings to our previous study on the gene response of gastric epithelial cells to H. pylori infection.ConclusionsCLDN1 was highly up-regulated in gastric cancer, and CLDN1 expression was independently associated with a poor post-operative prognosis, and may have important prognostic value. IL-8 and CLDN1 may represent central links between the gene response seen in acute H. pylori infection of gastric epithelial cells, and ultimately gastric cancer.
Highlights
The genetic changes in gastric adenocarcinoma are extremely complex and reliable tumor markers have not yet been identified
The aim of the current study was to identify the most differentially regulated genes in surgically resected gastric adenocarcinoma compared to matched normal mucosa, using whole genome cDNA microarray profiling
Rank product statistical testing [27] of the log2 fold change (FC) expression values of approximately 38000 genes on the microarray chip revealed 2297 genes that were significantly up-regulated and 2259 genes that were significantly down-regulated in the tumor tissue compared to matched normal mucosa (p < 0.01)
Summary
The genetic changes in gastric adenocarcinoma are extremely complex and reliable tumor markers have not yet been identified. Our aim was to identify the most differentially regulated genes in 20 gastric adenocarcinomas from a Norwegian selection, compared to matched normal mucosa, and we have related our findings to prognosis, survival and chronic Helicobacter pylori infection. Gastric adenocarcinoma is remarkably heterogeneous genetically, cytologically and architecturally compared to other gastrointestinal carcinomas. The Lauren classification divides adenocarcinomas into three different histological subtypes: intestinal and diffuse types and a mixed variant [9], which are thought to take different pathways of carcinogenesis. The mixed type shows non-homogenous mixtures of both intestinal and diffuse type architecture, and might represent a separate cancer category with exclusive gene mutations and a more aggressive course [14,15]. Mutations of cell-adhesion and angiogenic genes play important roles in the invasive and metastatic behavior of GC cells
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